In-line solvent re-use while guaranteeing yield and purity in a low-concentration process

Article published on 10 August 2019 Dominic Ormerod

Cyclisation, polymerization and enzymatic reactions often show substrate inhibition or precipitation of the substrate or of the reactant.  The typical high substrate concentrations in this type of reactions favour intermolecular reactions and lead to polymerisation of the substrate in the reaction medium or to the occurrence of other unwanted side-reactions, thereby seriously decreasing the yield to the desired product and the product purity.

For example, intramolecular macro-cyclisation reactions used in the production of active pharmaceutical ingredients, the synthesis of cyclic polymers, and enzymatic catalytic reactions typically suffer from low yields due to substrate precipitation and inhibition and declining catalytic activity. High dilutions are then set in to place to keep the selectivity up towards the desired end product and also to keep the purity of the end product high.

However, high substrate dilution involves the use of large amounts of solvent. When batch reactions are employed, frequently used solvent dilution rates for this type of reactions mount to 100-1000 l/mole of substrate to permit keeping substrate concentration sufficiently low. In other words, for the production of small quantities of an end product, the use of large volumes of solvent and the use of large reactor volumes is often required. This entails serious constraints for the industry. These reactions clearly also benefit from high dilution.

Although efforts including “Simulated high dilution conditions” were developed in the past, the use of still relatively large solvent volumes remains a point of attention. Associated with this is the limited reactor capacity. That's why using large reactor volumes for low productivity and small product yields is still necessary.

 

VID®

 

VITO developed a diluting substrate feed system enabling the controlled supply of a substrate – solvent mixture having a low substrate concentration, fairly independently of what the substrate concentration is in the feed solution, which may be significantly higher.  Because the high substrate dilution is only applied to the substrate volume which is actually supplied to the reactor, reactions which require high dilution of one or more to the substrates or reactants may be carried out using substantially reduced quantities of solvent, while relatively high reaction yields may be achieved, even in reactors having a relatively small volume.  This permits reducing the volume of solvent used in the process to 0.5 - 25 l/mol of substrate, while product yields achieved are typically as high as those achieved with reactions carried out at high dilution in large reaction volumes of 100-1000 L/mole of substrate.

By using a filtration membrane for the solvent recovery within the system, energy consumption otherwise needed to recover the solvent may be kept low compared to known and conventional techniques. Solvent recovery efficiency is typically rather low with the conventional techniques (only 50 – 80%), addition of extra chemicals as entrainers is sometimes required, and in many cases these operations are unsuitable for use with the reaction involved or the reaction conditions used.  As a consequence, the traditional solvent recovery operations are not suitable for direct coupling to a reactor, and may not provide continuous in-process solvent recovery.

By using a membrane, solvent recovery from the reaction mixture may be carried out at mild temperatures which may be of special importance in case of heat sensitive compounds, for example pharmaceutical active ingredients and functional food ingredients, in order to minimize the risk that they would lose their activity, texture and/or colour or would undergo thermal degradation.

Filtration membranes have predominantly been used as a separation member in post reaction purification processes. At VITO, at least one filtration membrane was incorporated in a diluting substrate feed system to successfully control a reaction, in particular the substrate supply thereto and the reaction outcome, in particular yield and selectivity.

A modular construction of the VITO device facilitates scaling up - an improved mass transfer may be guaranteed in comparison to known devices.

The membrane controlled supply of substrate into the reactor, and the separation and recycling of solvent from the mixture within the reaction vessel ensures highly increased product yield compared to standard high dilution reaction conditions presently used in industry.

 

With VID®, the following product yields were accomplished:

 

  • Mitsunobu lactonization to form a 13-membered ring
  • Biocatalyzed kinetic resolution based on the procedure published by M. Brossat et. al.: product inhibition of the enzyme is avoided because the concentration of acylated alcohol product in the solution of alcohol starting material is maintained at low concentration within the reactor
  • Barbier type reaction similar to that published by Li et. al.: a product yield of 70% was obtained at a conversion of 100%

 

Macrocyclisation case: PolyPeptide 

 

PolyPeptide Group is one of the world’s largest independent contract manufacturers of therapeutic peptides for the cosmetic, pharmaceutical and veterinary markets employing more than 800 people in six manufacturing sites.

To make the production of peptides run smoothly, PolyPeptide Group has joined forces with us. In the production of peptides large amounts of solvent are required.

To improve the efficiency of the synthesis process, we've applied our patented Volume Intensified Dilution, VID®. This technology ensures that the solvent is recycled continuously, reducing the amount required to 25% of the original amount.

The result: PolyPeptide's production process was made up to 75% more efficient.

Download the full research paper

Cyclic Peptide Formation in Reduced Solvent Volumes via In-Line
Solvent Recycling by Organic Solvent Nanofiltration

Dominic Ormerod Dominic Ormerod
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